title: Synergistic anti-tumor activity of isochaihulactone and paclitaxel on human lung cancer cells.
abstract: Drug resistance frequently develops in tumors during chemotherapy. Therefore, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Here, we show that isochaihulactone (K8) enhanced paclitaxel-induced apoptotic death in human lung cancer cells, and the enhancing effect was related to increased NSAID-activated gene-1 (NAG-1) expression. CalcuSyn software was used to evaluate the synergistic interaction of K8 and paclitaxel on human lung cancer cells; the synergistic effect of K8 in combination with paclitaxel was increased more than either of these drugs alone. Furthermore, the activity of ERK1/2 was enhanced by the combination of K8 and paclitaxel, and an ERK1/2 inhibitor dramatically inhibited NAG-1 expression in human lung cancer cells. Therefore, this synergistic apoptotic effect in human lung cancer cells may be directly associated with K8-induced NAG-1 expression through ERK1/2 activation. Moreover, over-expression of NAG-1 enhanced K8/paclitaxel-induced apoptosis in human lung cancer cells. In addition, treatment of nude mice with K8 combined with paclitaxel induced phospho-ERK1/2 and NAG-1 expression in vivo. Targeting of NAG-1 signaling could enhance therapeutic efficacy in lung cancer. Our results reveal that activation of NAG-1 by K8 enhanced the therapeutic efficacy of paclitaxel in human lung cancer cells via the ERK1/2 signaling pathway.
authors.affiliation: The PhD Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan. ylyu@mail.cmu.edu.tw
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Yu
authors.forename: Kuo-Jung
authors.initials: KJ
authors.lastname: Su
authors.forename: Cheng-Jueng
authors.initials: CJ
authors.lastname: Chen
authors.forename: Chyou-Wei
authors.initials: CW
authors.lastname: Wei
authors.forename: Ching-Ju
authors.initials: CJ
authors.lastname: Lin
authors.forename: Giou-Teng
authors.initials: GT
authors.lastname: Yiang
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.forename: Horng-Jyh
authors.initials: HJ
authors.lastname: Harn
authors.forename: Yi-Lin Sophia
authors.initials: YL
authors.lastname: Chen
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: D052117:Benzodioxoles; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C512868:isochaihulactone; D015107:4-Butyrolactone; D017239:Paclitaxel